M2 Macrophages are Major Mediators of Germline Risk of Endometriosis and Explain Pleiotropy With Comorbid Traits

Soledad Ochoa, Fernanda S. Rasquel‐Oliveira, Fernanda S Rasquel-Oliveira, Brett McKinnon, Marcela Haro, Sugarniya Subramaniam, Pak Yu, Simon G. Coetzee, Simon Coetzee, Michael S Anglesio, Kelly N Wright, Raanan Meyer, Anne E Porter, Caroline E Gargett, Sally Mortlock, Grant W Montgomery, Michael S Rogers, Kate Lawrenson
Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025 · vol. 12(41) , pp. e15285 · doi:10.1002/advs.202415285 · PMID:40938538 · W4414159502
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

M2 macrophages and IL1 signaling are identified as key mediators of endometriosis susceptibility and pleiotropy with comorbid traits, with IL1 inhibition showing therapeutic potential in preclinical models.

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Abstract

Endometriosis is a common gynecologic condition that causes chronic, life-altering symptoms including pain and infertility. There is an urgent need for new non-hormonal targeted therapeutics to treat endometriosis, but until very recently, the cellular and molecular signatures of endometriotic lesions are undefined, hindering the development of clinical advances. Integrating inherited risk data from analyses of >45 0000 individuals with ≈35 0000 single-cell transcriptomes from 21 patients, M2-macrophages as candidate drivers of disease susceptibility are uncovered, and nominating IL1 signaling as a central hub impacted by germline genetic variation associated with endometriosis risk. Extensive functional follow-up confirmed these associations and revealed a pleiotropic role for this pathway in endometriosis. Population-scale expression quantitative trait locus analysis demonstrates that genetic variation controlling IL1A expression is associated with endometriosis risk variants. Manipulation of IL1 signaling in state-of-the-art in vitro decidualized endometrial organoids impacts epithelial differentiation, and in an in vivo endometriosis model, treatment with anakinra (an interleukin-1 receptor antagonist) results in a significant, dose-dependent reduction in spontaneous and evoked pain and dampened pro-angiogenic signaling. Together, these studies highlight non-diagnostic cell types as central to endometriosis susceptibility and support IL1 signaling as an important actionable pathway for this disease.

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Outcome instruments

rASRM

Condition tags

mesh:D004715endometriosisinfertility

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Macrophages Macrophages Macrophages

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Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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